human lysozyme; amyloidogenic variants; camel antibody fragments; hydrogen/deuterium exchange; stabilization
Abstract :
[en] One of the 20 or so human amyloid diseases is associated with the deposition in vital organs of full-length mutational variants of the antibacterial protein lysozyme. Here, we report experimental data that permit a detailed comparison to be made of the behaviour of two of these amyloidogenic variants, I56T and D67H, under identical conditions. Hydrogen/deuterium exchange experiments monitored by NMR and mass spectrometry reveal that, despite their different locations and the different effects of the two mutations on the structure of the native state of lysozyme, both mutations cause a cooperative destabilisation of a remarkably similar segment of the structure, comprising in both cases the beta-domain and the adjacent C-helix. As a result, both variant proteins populate transiently a closely similar, partially unstructured intermediate in which the beta-domain and the adjacent C-helix are substantially and simultaneously unfolded, whereas the three remaining a-helices that form the core of the a-domain still have their native-like structure. We show, in addition, that the binding of a camel antibody fragment, cAb-HuL6, which was raised against wild-type lysozyme, restores to both variant proteins the stability and cooperativity characteristic of the wild-type protein; as a consequence, it inhibits the formation of amyloid fibrils by both variants. These results indicate that the reduction in global cooperativity, an associated ability to populate transiently a specific, partly unfolded intermediate state under physiologically relevant conditions, is a common feature underlying the behaviour of these two pathogenic mutations. The formation of intermolecular interactions between lysozyme molecules that are in this partially unfolded state is therefore likely to be the fundamental trigger of the aggregation process that ultimately leads to the formation and deposition in tissue of amyloid fibrils. (C) 2004 Elsevier Ltd. All rights reserved.
Canet, Denis; University of Oxford > Chemistry Research Laboratory > Oxford Centre for Molecular Sciences
Last, Alexander M.; University of Oxford > Chemistry Research Laboratory > Oxford Centre for Molecular Sciences
Pardon, Els; Vrije Universiteit Brussel > Vlaams Interuniversitair Instituut voor Biotechnologie > Department of Molecular and Cellular InteractionsLaboratorium voor Ultrastructuur
Archer, David B.; University of Nottingham > School of Biology
Muyldermans, Serge; Vrije Universiteit Brussel > Vlaams Interuniversitair Instituut voor Biotechnologie > Department of Molecular and Cellular InteractionsLaboratorium voor Ultrastructuur
Wyns, Lode; Vrije Universiteit Brussel > Vlaams Interuniversitair Instituut voor Biotechnologie > Department of Molecular and Cellular InteractionsLaboratorium voor Ultrastructuur
Matagne, André ; Université de Liège - ULiège > Département des sciences de la vie > Laboratoire d'Enzymologie et Repliement des Protéines, Centre d'Ingénierie des Protéines
Robinson, Carol V.; University of Cambridge > Department of Chemistry
Redfield, Christina; University of Oxford > Chemistry Research Laboratory > Oxford Centre for Molecular Sciences
Dobson, Christopher M.; University of Cambridge > Department of Chemistry
Language :
English
Title :
Reduced global copperativity is a common feature underlying the amyloidogenicity of pathogenic lysozyme mutations
Publication date :
25 February 2005
Journal title :
Journal of Molecular Biology
ISSN :
0022-2836
eISSN :
1089-8638
Publisher :
Academic Press Ltd Elsevier Science Ltd, London, United Kingdom
M. Sunde, and C.C.F. Blake From the globular to the fibrous state: protein structure and structural conversion in amyloid formation Quart. Rev. Biophys. 31 1998 1 39
F. Chiti, P. Webster, N. Taddei, A. Clark, M. Stefani, G. Ramponi, and C.M. Dobson Designing conditions for in vitro formation of amyloid protofilaments and fibrils Proc. Natl Acad. Sci. USA 96 1999 3590 3594
C.M. Dobson Protein misfolding, evolution and disease Trends Biochem. Sci. 24 1999 329 332
M. Fandrich, M.A. Fletcher, and C.M. Dobson Amyloid fibrils from muscle myoglobin Nature 410 2001 165 166
J.I. Guijarro, M. Sunde, J.A. Jones, I.D. Campbell, and C.M. Dobson Amyloid fibril formation by an SH3 domain Proc. Natl Acad. Sci. USA 95 1998 4224 4228
D. Schenk Amyloid-beta immunotherapy for Alzheimer's disease: the end of the beginning Nature Rev. Neurosci. 3 2002 824 828
J.C. Sacchettini, and J.W. Kelly Therapeutic strategies for human amyloid diseases Nature Rev. Drug Discov. 1 2002 267 275
C.M. Dobson Protein folding and disease: a view from the first Horizon symposium Nature Rev. Drug Discov. 2 2003 154 160
M.B. Pepys, P.N. Hawkins, D.R. Booth, D.M. Vigushin, G.A. Tennent, and A.K. Soutar Human lysozyme gene mutations cause hereditary systemic amyloidosis Nature 362 1993 553 557
S. Valleix, S. Drunat, J.B. Philit, D. Adoue, J.C. Piette, and D. Droz Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family Kidney Int. 61 2002 907 912
M. Yazaki, S.A. Farrell, and M.D. Benson A novel lysozyme mutation Phe57Ile associated with hereditary renal amyloidosis Kidney Int. 63 2003 1652 1657
J. Funahashi, K. Takano, K. Ogasahara, Y. Yamagata, and K. Yutani The structure, stability, and folding process of amyloidogenic mutant human lysozyme J. Biochem. (Tokyo) 120 1996 1216 1223
D.R. Booth, M. Sunde, V. Bellotti, C.V. Robinson, W.L. Hutchinson, and P.E. Fraser Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis Nature 385 1997 787 793
D. Canet, M. Sunde, A.M. Last, A. Miranker, A. Spencer, C.V. Robinson, and C.M. Dobson Mechanistic studies of the folding of human lysozyme and the origin of amyloidogenic behavior in its disease-related variants Biochemistry 38 1999 6419 6427
L.A. Morozova-Roche, J. Zurdo, A. Spencer, W. Noppe, V. Receveur, and D.B. Archer Amyloid fibril formation and seeding by wild-type human lysozyme and its disease-related mutational variants J. Struct. Biol. 130 2000 339 351
A.K. Chamberlain, V. Receveur, A. Spencer, C. Redfield, and C.M. Dobson Characterization of the structure and dynamics of amyloidogenic variants of human lysozyme by NMR spectroscopy Protein Sci. 10 2001 2525 2530
K. Takano, J. Funahashi, and K. Yutani The stability and folding process of amyloidogenic mutant human lysozymes Eur. J. Biochem. 268 2001 155 159
D. Canet, A.M. Last, P. Tito, M. Sunde, A. Spencer, and D.B. Archer Local cooperativity in the unfolding of an amyloidogenic variant of human lysozyme Nature Struct. Biol. 9 2002 308 315
S. Muyldermans Single domain camel antibodies: current status J. Biotechnol. 74 2001 277 302
M. Dumoulin, K. Conrath, A. Van Meirhaeghe, F. Meersman, K. Heremans, and L.G. Frenken Single-domain antibody fragments with high conformational stability Protein Sci. 11 2002 500 515
S. Hooke, S.J. Eyles, A. Miranker, S.E. Radford, C.V. Robinson, and C.M. Dobson Cooperative elements in protein folding monitored by electrospray ionization mass spectrometry J. Am. Chem. Soc. 117 1995 7548 7549
M. Dumoulin, A.M. Last, A. Desmyter, K. Decanniere, D. Canet, and G. Larsson A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme Nature 424 2003 783 788
Y. Bai, J.S. Milne, L. Mayne, and S.W. Englander Primary structure effects on peptide group hydrogen exchange Proteins: Struct. Funct. Genet. 17 1993 75 86
J.D. Harper, and P.T. Lansbury Jr Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins Annu. Rev. Biochem. 66 1997 385 407
S.W. Englander Protein folding intermediates and pathways studied by hydrogen exchange Annu. Rev. Biophys. Biomol. Struct. 29 2000 213 238
C.M. Dobson Protein folding and misfolding Nature 426 2003 884 890
V.W. DeLaGarza Pharmacologic treatment of Alzheimer's disease: an update Am. Fam. Physician 68 2003 1365 1372
F.E. Cohen, and J.W. Kelly Therapeutic approaches to protein-misfolding diseases Nature 426 2003 905 909
C.M. Dobson In the footsteps of alchemists Science 304 2004 1259 1262
S.D. Hooke, S.E. Radford, and C.M. Dobson The refolding of human lysozyme: a comparison with the structurally homologous hen lysozyme Biochemistry 33 1994 5867 5876
E. Frare, P. Polverino de Laureto, J. Zurdo, C.M. Dobson, and A. Fontana A highly amyloidogenic region of hen lysozyme J. Mol. Biol. 340 2004 1153 1165
M. Dumoulin, and C.M. Dobson Probing the origins, diagnosis and treatment of amyloid diseases using antibodies Biochimie 86 2004 589 600
M. Bouchard, J. Zurdo, E.J. Nettleton, C.M. Dobson, and C.V. Robinson Formation of insulin amyloid fibrils followed by FTIR simultaneously with CD and electron microscopy Protein Sci. 9 2000 1960 1967
A. Spencer, L.A. Morozov-Roche, W. Noppe, D.A. MacKenzie, D.J. Jeenes, and M. Joniau Expression, purification, and characterization of the recombinant calcium-binding equine lysozyme secreted by the filamentous fungus Aspergillus niger: comparisons with the production of hen and human lysozymes Protein Expr. Purif. 16 1999 171 180
Woodruff, N. D. (1998). Investigation of protein structure and folding by NMR spectroscopy. PhD thesis, University of Oxford.
R. Koradi, M. Billeter, and K. Wuthrich MOLMOL: a program for display and analysis of macromolecular structures J. Mol. Graph. 14 1996 29 32